Clinical Genetic Studies of Familial and Hereditary Cancer Syndromes

家族性和遗传性癌症综合征的临床遗传学研究

基本信息

批准号：
8349569
负责人：
MARK H GREENE
金额：
$ 399.76万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8349569
关键词：
Acute Myelocytic Leukemia Adrenal Gland Cancer Advocacy Affect Age American Aplastic Anemia Award BAK1 gene BRCA1 gene BRCA2 gene Behavior Behavioral Biogenesis Biological Bone Marrow Transplantation Bone Tissue Cancer Family Cancer-Predisposing Gene Candidate Disease Gene Caring Cervical Clinical Cloning Collaborations Collection Colonic Polyps Color Communities Consent Costello syndrome Counseling DICER1 gene DNA Data Decision Making Development Diamond Diamond-Blackfan anemia Disease Dissection Division of Cancer Epidemiology and Genetics Dyskeratosis Congenita Dysmyelopoietic Syndromes Educational workshop Employee Strikes Enrollment Epidemiology Epithelial Cells Eye Family Family Study Family member Fanconi&apos s Anemia Foundations General Population Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic screening method Genomics Germ-Line Mutation German population Grant Gynecologic Oncology Group HRAS gene Hand Hereditary Breast Carcinoma Hereditary Breast and Ovarian Cancer Syndrome Hereditary Malignant Neoplasm Hereditary Neoplastic Syndromes Histopathology Hormones Human Human Papillomavirus Inborn Genetic Diseases Individual Inherited Institutional Review Boards International Investigation KITLG gene KRAS2 gene Kidney Neoplasms Laboratories Lead Learning Li-Fraumeni Syndrome Lymphoma Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of ovary Malignant neoplasm of testis Maps Methods MicroRNAs Modality Modeling Moods Multiple Hamartoma Syndrome Mutate Mutation Myotonic Dystrophy Neoplasms Neurofibromatosis 1 Neutropenia Noonan Syndrome Oncogenes Operative Surgical Procedures Ovarian PTEN gene Pancytopenia Pathogenicity Pathway Analysis Patients Peer Review Penetrance Phenotype Pituitary Neoplasms Pleuropulmonary Blastoma Population Predisposition Protocols documentation Publications Publishing Radial Rare Diseases Registries Reporting Research Research Activity Research Personnel Resources Risk Risk Reduction Role Sampling Schedule Screening for cancer Screening procedure Series Social Network Solid Neoplasm Staging Surface Susceptibility Gene Syndrome TP53 gene Technology Test Result Thrombocytopenia Time Tissue Banks Training Translational Research Tumor Suppressor Genes Tumor Tissue United States National Institutes of Health Variant anticancer research base bench to bedside cancer diagnosis cancer genetics cancer prevention cancer risk clinical phenotype cohort developmental disease early experience early onset epidemiologic data epidemiology study follow-up genetic analysis genetic epidemiology genetic risk assessment genome wide association study high risk immune function in vitro Assay in vivo kindred malignant breast neoplasm member multidisciplinary mutation carrier next generation novel osteosarcoma phosphodiesterase 11a prospective psychosocial reproductive epidemiology research clinical testing sarcoma soft tissue telomere tool

项目摘要

The Clinical Genetics Branch (CGB) is NCI's base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators. Hereditary Breast/Ovarian Cancer (HBOC) [CAS 8040] is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples [NCI Protocol #02-C-0212]. Research highlights include a series of important positive, and definitive-negative candidate gene studies analyzing genetic modifiers of BRCA1/2-related breast cancer risk as part of the Consortium of Investigators of Modifiers of BRCA1 (CIMBA) project, and a series of counseling/psychosocial reports of our early experience with HBOC families undergoing genetic risk assessment. With a mean prospective follow-up of 17.7 years for 395 mutation-negative family members, we observed no excess breast cancer risk compared with the general population. We are developing new laparoscopic tissue collection methods for in vivo collection of human ovarian surface epithelial cells for translational research purposes [CAS 10376], with very promising ovarian epithelial cell yields. Inherited Bone Marrow Failure Syndromes (IBMFS) Study [CAS 7130] targets Fanconi anemia (FA) and related disorders with a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. This is the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders. We enrolled 1400 members from 350 families. Major findings include quantitative estimates of FA- and dyskeratosis congenita (DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders, expanding the clinical phenotype of these disorders, and identifying very short telomeres as pathognomonic for DC. Under a grant from the Fanconi Anemia Research Foundation, we are studying immune function in FA patients [CAS 10475]. We have collaboratively analyzed cancer risks in the the North American, German and Israeli FA cohorts, and reported similar data from the NCI cohort. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have analyzed the North American Diamond- Blackfan Registry (DBAR) and documented for the first time significant risks of cancer, particularly osteogenic sarcoma, in DBA. A closely-related project, Cancer in Rare Developmental Disorders [CAS 10549] is in its early stages of development. It leverages the observation that some oncogenes and tumor suppressor genes that are somatically altered in tumor tissue have also been found to be mutated in the germline of individuals with inherited conditions, e.g. Noonan (KRAS), Costello (HRAS) and Cowden syndromes (PTEN). Interdisciplinary dissection of such rare associations may lead to the focused identification of novel cancer genes. Thus, we will study rare developmental syndromes that are associated with cancer. Familial Testicular Cancer [CAS 7070, 7130] is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families [NCI Protocol #02-C-0178], the other aimed at mapping and cloning new TGCT susceptibility genes [NCI Protocol #04-C-N076]. Through the former, we have enrolled 609 consented members from 119 newly-ascertained families. This multidisciplinary, etiologically-oriented family study has found that testicular microlithiasis is more common than expected in TGCT kindred, recognized a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lymphomas and lentigenes, and identified germline mutations in the PDE11A gene as modifier of FTGCT risk. We are the second largest contributor to International Testicular Cancer Linkage Consortium, through which we published a descriptive analysis of 469 TGCT families (containing 1002 TGCT cases), and documented that age-at-cancer-diagnosis is significantly younger in familial versus sporadic TGCT. Analyses of the histopathology of familial versus sporadic TGCT, and quantification of the risk of cancers other than TGCT in multiple-case families are nearing completion. As part of DCEGs Rare Cancers iSELECT project, we have confirmed strong associations between familial TGCT risk and 4 genomic regions recently implicated in GWAS analyses, i.e., KITLG, BAK1, DMRT1, and TERT-CLPTM1L. A family-based familial TGCT GWAS is under analysis, with a special focus on copy number variants. These data are also being pooled with those from a sporadic TGCT GWAS currently under analysis by colleagues in the Hormone and Reproductive Epidemiology Branch, DCEG. BR> The Li-Fraumeni Syndrome (LFS) [CAS 10503], originally identified by DCEG investigators 40 years ago is a rare, inherited disorder caused by germline TP53 mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. After a long hiatus, we have initiated a new LFS study which will conduct comprehensive clinical evaluations, provide genetic counseling and testing, investigate cancer screening modalities, identify genetic modifiers, study cancer risk-reduction strategies, and search for the genetic etiology in the 30% of affected patients without a TP53 mutation. An international workshop is scheduled for November 2010, to launch the activities of a newly-formed consortium for the study of LFS, and to mobilize the LFS advocacy community. Familial Pleuropulmonary Blastoma (PPB) [CAS 10548] is a newly-described syndrome caused by germline mutations in DICER1; it represents the first known cancer predisposition syndrome caused by altered microRNA biogenesis. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which made this remarkable observation, as a means to engage in the cutting-edge domain of miRNA research and introduce this technology into DCEG's research armamentarium. We will focus on more precisely defining the clinical phenotype of this remarkable disorder, in a new project that has just been submitted for IRB review. Neurofibromatosis 1 [CAS 10567] is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of CGB's research portfolio, which has yielded more than 30 peer-reviewed publications. A series of projects are actively underway as part of each familial cancer study being conducted by the Branch. We are developing new genetic counseling tools (e.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.

临床遗传学分部 (CGB) 是 NCI 开展校内临床癌症遗传学转化研究活动的基地。 CGB 带来了多学科、流行病学的视角：了解基因在癌症病因、治疗和预防中的作用；为高风险个人和家庭制定综合管理策略；培训下一代临床癌症遗传学研究人员。遗传性乳腺癌/卵巢癌 (HBOC) [CAS 8040] 基于 33 个 BRCA 突变阳性家庭的前瞻性队列，具有广泛的临床/流行病学数据和生物样本 [NCI Protocol #02-C-0212]。研究亮点包括一系列重要的阳性和明确阴性候选基因研究，分析 BRCA1/2 相关乳腺癌风险的基因修饰物，作为 BRCA1 修饰物研究者联盟 (CIMBA) 项目的一部分，以及一系列咨询/我们对 HBOC 家庭进行遗传风险评估的早期经历的心理社会报告。通过对 395 名突变阴性家庭成员进行平均 17.7 年的前瞻性随访，我们发现与普通人群相比，乳腺癌风险并未升高。我们正在开发新的腹腔镜组织采集方法，用于体内采集人卵巢表面上皮细胞用于转化研究目的 [CAS 10376]，卵巢上皮细胞产量非常有希望。遗传性骨髓衰竭综合征 (IBMFS) 研究 [CAS 7130] 针对范可尼贫血 (FA) 和相关疾病，特别是再生障碍性贫血、骨髓增生异常综合征 (MDS)、急性髓系白血病 (AML) 和选定的实体瘤。这是对这些罕见疾病的首次以流行病学为基础、以病因学为重点的调查。我们招募了来自 350 个家庭的 1400 名会员。主要发现包括对 FA 和先天性角化不良 (DC) 相关癌症风险的定量估计，确定这两种疾病的癌症风险惊人的相似性，扩大这些疾病的临床表型，以及确定非常短的端粒作为 DC 的特征。在范可尼贫血研究基金会的资助下，我们正在研究 FA 患者的免疫功能 [CAS 10475]。我们合作分析了北美、德国和以色列 FA 队列的癌症风险，并报告了 NCI 队列的类似数据。我们合作开发了一种体外检测方法，用于检测 FANCD1/BRCA2 中意义不明的错义变异的致病性。我们分析了北美 Diamond-Blackfan 登记处 (DBAR)，并首次记录了 DBA 中癌症（特别是成骨肉瘤）的重大风险。一个密切相关的项目，罕见发育障碍中的癌症 [CAS 10549] 正处于开发的早期阶段。它利用了这样的观察结果：在肿瘤组织中体细胞改变的一些癌基因和肿瘤抑制基因也被发现在患有遗传性疾病的个体的种系中发生突变，例如，努南 (KRAS)、科斯特洛 (HRAS) 和考登综合征 (PTEN)。对这种罕见关联的跨学科剖析可能会导致新癌症基因的集中鉴定。因此，我们将研究与癌症相关的罕见发育综合征。家族性睾丸癌 [CAS 7070, 7130] 是一种研究不足的家族性癌症疾病，正在 2 个方案下进行评估，一个方案产生新的多病例家族 [NCI 方案 #02-C-0178]，另一个旨在定位和克隆新的 TGCT易感基因 [NCI 方案#04-C-N076]。通过前者，我们已经招募了来自 119 个新确定家庭的 609 名同意成员。这项多学科、以病因学为导向的家庭研究发现，睾丸微石症在 TGCT 亲属中比预期更常见，认识到可能是一种新的 FTGCT 综合征，其特征为肾和垂体肿瘤、结肠息肉、淋巴瘤和雀斑，并确定了 PDE11A 基因的种系突变作为 FTGCT 风险的修饰符。我们是国际睾丸癌连锁联盟的第二大贡献者，通过该联盟，我们发表了对 469 个 TGCT 家族（包含 1002 个 TGCT 病例）的描述性分析，并记录了家族性 TGCT 与散发性 TGCT 相比，癌症诊断年龄明显更年轻。家族性 TGCT 与散发性 TGCT 的组织病理学分析以及多病例家族中 TGCT 以外癌症风险的量化已接近完成。作为 DCEG 罕见癌症 iSELECT 项目的一部分，我们已经证实家族 TGCT 风险与最近 GWAS 分析涉及的 4 个基因组区域（即 KITLG、BAK1、DMRT1 和 TERT-CLPTM1L）之间存在密切关联。一项基于家族的家族 TGCT GWAS 正在分析中，特别关注拷贝数变异。这些数据还与 DCEG 激素和生殖流行病学部门的同事目前正在分析的零星 TGCT GWAS 数据进行了汇总。 BR> Li-Fraumeni 综合征 (LFS) [CAS 10503] 最初由 DCEG 研究人员在 40 年前发现，是一种由种系 TP53 突变引起的罕见遗传性疾病，会增加早发性骨和软组织肉瘤、乳腺癌、肾上腺癌和脑癌。经过长时间的中断，我们启动了一项新的 LFS 研究，该研究将进行全面的临床评估，提供遗传咨询和检测，研究癌症筛查方式，识别遗传修饰因子，研究降低癌症风险的策略，并寻找 30 个国家的遗传病因。没有 TP53 突变的受影响患者的百分比。国际研讨会定于 2010 年 11 月举行，旨在启动新成立的 LFS 研究联盟的活动，并动员 LFS 倡导团体。家族性胸膜肺母细胞瘤 (PPB) [CAS 10548] 是一种新描述的由 DICER1 种系突变引起的综合征；它代表了第一个已知的由 microRNA 生物发生改变引起的癌症易感综合症。利用 NIH Bench-to-Bedside 奖项，我们与做出这一非凡观察的研究小组建立了合作关系，以此作为参与 miRNA 研究前沿领域并将该技术引入 DCEG 的研究设备的一种手段。在刚刚提交 IRB 审查的新项目中，我们将专注于更精确地定义这种显着疾病的临床表型。神经纤维瘤病 1 [CAS 10567] 是一种典型的遗传性癌症易感性疾病。我们正在进一步定义其表型并寻找 NF1 外显率的遗传修饰剂。家族性癌症的遗传咨询、心理社会和行为研究是 CGB 研究组合的重要组成部分，该研究组合已发表 30 多篇经过同行评审的出版物。作为该分会开展的每项家族癌症研究的一部分，一系列项目正在积极开展。我们正在开发新的遗传咨询工具（例如彩色生态遗传学关系图），应用新的分析策略，例如社交网络分析，分析与选择手术或 GOG-199 中筛查相关的变量，评估骨髓移植决策的决定因素-在 FA 家族内进行研究，并探索模糊的筛查测试结果对 BRCA1/2 突变携带者的情绪和筛查行为的影响（例如，彩色生态遗传学关系图），应用新颖的分析方法策略，例如社交网络分析，分析与 GOG-199 中选择手术或筛查相关的变量，评估 FA 家族内骨髓移植决策的决定因素，以及探索模糊的筛查测试结果对情绪和筛查行为的影响BRCA1/2突变携带者。